New exploration on pathogenesis and early diagnosis of gestational diabetes

Abstract

Gestational diabetes mellitus (GDM) refers to varying degrees of abnormal glucose metabolism that occur during pregnancy and excludes patients previously diagnosed with diabetes. GDM is a unique among the four subtypes of diabetes classified by the international World Health Organization standards. Although GDM patients constitute a small proportion of the total number of diabetes cases, the incidence of GDM has risen significantly over the past decade, posing substantial risk to pregnant women and infants. Therefore, it warrants considerable attention. The pathogenesis of GDM is generally considered to resemble that of type II diabetes, though it may have distinct characteristics. Analyzing blood biochemical proteins in the context of GDM can help elucidate its pathogenesis, thereby facilitating more effective prevention and management strategies. This article reviews this critical clinical issue to enhance the medical community's sufficient understanding of GDM.

Key Words: Gestational diabetes mellitus; Pathogenesis; Proteomics; RBP4; ANGPTL8

Core Tip: Pancreas β cellular damage and tissue insulin resistance are key to the pathogenesis of gestational diabetes mellitus (GDM). Once beta cell dysfunction begins, hyperglycemia, insulin resistance, and further beta cell dysfunction are likely to enter a vicious cycle. Introducing advanced biotechnology such as proteomics for basic research on GDM is a good attempt. RBP4 and ANGPTL8 proteins may play a role in the pathogenesis of GDM, but there is insufficient evidence to diagnose GDM by detecting the two proteins.

INTRODUCTION

In this editorial, we comment on a retrospective research paper by Cao et al[1], published in the latest issue of the World Journal of Clinical Cases. The authors used quantitative proteomics to detect differential protein expression in the blood of patients with gestational diabetes mellitus (GDM). Their goal was to explore the pathogenesis and characteristics of GDM and to identify potential biomarkers to predict its occurrence. Proteomics is the study of protein composition and its changes in cells, tissues, or organisms. This research includes analyzing protein expression levels, post-translational modifications, and protein-protein interactions[2]. The pathogenesis of GDM may involve abnormalities in lipid metabolism, activation of the coagulation cascade, the complement system, and various inflammatory response factors. Numerous proteins are also implicated. The author tested 47 proteins and found that two had significantly increased expression and certain specificity. These two proteins may have significant implications for the early diagnosis and understanding of GDM pathogenesis. Proteomics is a central focus of life sciences in the post genomic era. Complex post-translational modifications, subcellular localization or migration, and protein-protein interactions are challenging to determine at the mRNA level, necessitating the development of high-throughput and high-sensitivity research technologies. Proteomics techniques have filled these gaps. Techniques such as two dimensional gel electrophoresis, isoelectric focusing, biological mass spectrometry and non-gel technologies are all related to proteomics. In clinical practice, these technologies typically involve comparing and analyzing the protein mass spectrometry profiles in the serum of patients with the disease under study. Identifying differential proteins and using analysis software like Biomarker Pattern to establish relevant classification tree models are essential steps in this process[3]. The team conducting this study on GDM achieved promising results using these analytical techniques. This represents a positive step for the application of proteomics in interdisciplinary diseases within clinical medicine and obstetrics and gynecology.

THE COMPLEXITY AND DIVERSITY OF DIABETES PATHOGENESIS

Diabetes is a polygenic, genetically heterogeneous disease caused by a combination of genetic and environmental factors. Type I diabetes mellitus typically has a genetic abnormality background, where the destruction of pancreatic islets β-cells leads to absolute insulin deficiency, often mediated by abnormal immune factors. Type II diabetes mellitus (T2DM) is characterized by insulin resistance and an absolute or relative insufficiency of insulin secretion, primarily due to environmental factors such as excessive nutrition, obesity, insufficient physical activity, aging, long-term stress, and exposure to chemical toxins. Genetic factors also play a secondary role in T2DM, increasing genetic susceptibility and affecting certain aspects of glucose metabolism, though they are not necessary for the onset of the disease. Insulin resistance is now believed to be a hallmark of T2DM and is likely the initiating factor in its development. Both lipid overload and chronic inflammation can cause insulin resistance. Increased adipocyte levels in patients elevate the levels of free fatty acids and their metabolites in the blood and within pancreatic islet β-cells and muscle cells, inhibiting insulin signal transduction. Additionally, the inactivation of inflammatory proteins produced by macrophages can improve diet induced diabetes, while dietary fat promotes pathological insulin resistance through chronic inflammation[4]. Excessive adipocytes attract macrophages and secrete inflammatory signaling molecules such as TNF-α and IL-6, which block insulin signal transduction in skeletal muscle through JNK. These mechanisms overlap and interact, leading to insulin resistance.

The dysfunction of pancreaticislet β cells is crucial in the pathogenesis of T2DM. Defective β-cells lead to abnormal insulin secretion in terms of both quality and quantity, as well as disrupted insulin secretion patterns. The pathogenesis of T2DM progresses from impaired fasting glucose and impaired glucose tolerance to the appearance of clinical symptoms. Genetic abnormalities typically determine the initial factors causing structural and functional abnormalities of β-cells. These involve gene such as HLA, CTLA4, GCK, PTPN22, INS, and IL-2RA. Genome-wide association studies of T2DM have identified hundreds of genetic variants in non-coding and β-cell regulatory genomic regions. Walker et al[5] focused on β-cell hub gene and transcription factor RFX6, finding that multilayer genetic risks converge on RFX6-mediated networks, reducing insulin secretion. Other important factors influencing T2DM pathogenesis include abnormal mitochondrial function, disrupted tricarboxylic acid (TCA) cycle, abnormal triglyceride/free fatty acid cycle, oxidative stress of endoplasmic reticulum, chronic inflammation of islets, deposition of fat and other harmful substances in islets, low differentiation and transdifferentiation of β-cells, and abnormal endocrine hormone levels in patients. Additionally, the brain-centered glucose regulation system can lower blood glucose levels through both insulin-dependent and insulin-independent mechanisms. Reduced glucose availability also significantly impacts diabetes pathogenesis[6]. The dysfunction of pancreatic islet α-cells, deficiency of incretin secretion, and abnormal intestinal flora structure and function are also related to T2DM pathogenesis.

EXPLORING THE MECHANISM OF GDM

High-risk pregnant women prone to GDM are typically older, have positive urine glucose tests, obese, have a family history of diabetes, and experience persistent mental stress. The diagnosis of GDM requires an oral glucose tolerance test between 24 and 28 weeks of pregnancy. Women diagnosed with diabetes before pregnancy are considered to have diabetes complicated by pregnancy, which is beyond the scope of this discussion. Since the occurrence of GDM is similar to that of T2DM, understanding the pathogenesis of T2DM can provide significant insights into the pathogenesis of GDM. Although glucose metabolism in GDM patients may return to normal after delivery, a small number of patients can develop permanent diabetes. During early pregnancy, as gestational age increases, the fetus’s demand for nutrients rises. Concurrently, estrogen and progesterone increase the mother’s glucose utilization, causing her plasma glucose levels to decrease as pregnancy progresses[7]. In the second and third trimesters, anti-insulin substances in pregnant women increase, and the sensitivity of these chemicals decreases with advancing gestational age. Hormones such as estrogen, progesterone, leptin, cortisol, placental prolactin, and placental growth hormone collectively promote insulin resistance[8]. To maintain normal glucose metabolism, the demand for insulin must increase accordingly. If a pregnant woman has limited insulin secretion, GDM may occur if physiological changes during pregnancy cannot compensate and blood sugar levels rise. Chen et al[9] found that TET3 dysfunction in oocytes caused maternal inheritance of glucose intolerance, and defects or abnormalities in the glucokinase gene may be related to the pathogenesis of GDM.

Pregnancy can cause latent diabetes to manifest, lead to the development of GDM in women without prior diabetes, and exacerbate pre-existing diabetes. Cao et al[1] identified 215 differentially expressed proteins in GDM patients. Of these, the isotopic tags for relative and absolute quantification (iTRAQ) ratios of 47 proteins were significantly different, being greater than 1.50 or less than 0.67. Compared to healthy women, 31 proteins had increased expression in GDM pregnancies, while 16 proteins had decreased expression. The researchers divided the subjects into GDM and normal control groups according to IADPSG diagnostic criteria and used bioinformatics analysis to identify the key proteins and signaling pathways related to GDM. Venkatesh et al[10] retrospectively analyzed 1560822 cases of GDM in United States and found an increased frequency of various adverse pregnancy outcomes in these women. Specifically, there was a significant increase in the incidence of pre-eclampsia, premature delivery, and admission to the neonatal intensive care unit. Differences in adverse outcomes persisted across different racial groups. The impact of GDM on both mother and fetus depends on the quality of diabetes control. Poor blood sugar control significantly increases the risk of complications for both mother and fetus. Paolino et al[11] found that babies born to mothers with GDM had increased birth weight and C-peptide levels. Regardless of dietary regulation or insulin therapy, the number of Treg cells in the placentas of women with GDM decreased. They suggested that RANK signaling in thymic epithelium and natural Treg cells is central to pregnancy immunity and metabolic maternal adaptation. Human pregnancy is associated with progressive insulin resistance, which may manifest as dominant GDM if not compensated.

The changes in glucose metabolism during pregnancy are complex, and the potential mechanisms of GDM include abnormal endocrine hormones in the uterus, disrupted TCA cycle, oxidative stress in endoplasmic reticulum, fat overload and expansion, chronic immune inflammation, abnormal gluconeogenesis and oxidative stress, chronic damage to islet structure and deposition of harmful substances, and the inability of pancreatic β-cells to compensate for chronic energy demands, eventually leading to insulin resistance[1]. β-cell injury and tissue insulin resistance are central to the pathogenesis of GDM. When β cells lose the ability to accurately perceive blood glucose concentrations or cannot release sufficient insulin, β cell dysfunction occurs. Insulin resistance exacerbates this dysfunction, reducing insulin-stimulated glucose uptake and further leading to hyperglycemia. In response, β-cells must produce extra insulin. Insulin resistance often results from the failure of insulin signal transduction, leading to inadequate translocation of glucose transporter 4 to the plasma membrane. Once β-cell dysfunction begins, a vicious cycle of hyperglycemia, insulin resistance, and further β-cell dysfunction is likely to ensue.

THE ROLE OF RBP4 AND ANGPTL8 PROTEINS IN THE PATHOGENESIS OF GDM

RBP4 and ANGPTL8 are proteins synthesized by the liver and adipose tissue. Serum RBP4 levels are usually closely related to body weight and glucose sensitivity, with RBP4 affecting insulin function by regulating fat metabolism. There is a strong correlation between RBP4 levels and decreased blood flow-regulated vasodilation, increased urinary albumin excretion rate, and retinopathy, suggesting that serum RBP4 Levels can serve as a reference index for complications of type 2 diabetes. Wu et al[12] conducted a case-control study on 332 patients with GDM and 664 matched controls. After adjusting the multivariate model of potential risk factors, the OR for the extreme quartile of serum RBP4 level was 2.26, indicating that each standard deviation increment of RBP4 was associated with a 1.39 times higher risk of GDM. ANGPTL8 is involved in the regulation of lipid metabolism and triglyceride homeostasis, playing a role in the upstream or internal regulation of protein processing and lipoprotein metabolism. Abdeltawab et al[13] found that, compared with healthy pregnant women, levels of miRNA-223 and ANGPTL8 were significantly increased in women with GDM. MiRNA-223 and ANGPTL8 were also significantly correlated with each other and with total cholesterol and triglycerides. These findings support the hypothesis that miRNA-223 and ANGPTL8 are involved in the pathogenesis of GDM, suggesting that ANGPTL8 may be used for early diagnosis of the condition.

The scholars of the above study also found[1] a significant increase in RBP4 and ANGPTL8 proteins in the blood of pregnant women with GDM. The expression levels of RBP4 and ANGPTL8 proteins in the serum of these pregnant women were detected by ELISA, consistent with the results of mass spectrometry experiments, indicating certain sensitivity. Since both proteins are associated with insulin resistance, it is speculated that they are closely related to the pathogenesis of GDM. Some researchers believe that the level of ANGPTL8 in early pregnancy is significantly and independently correlated with the risk of developing GDM at 24-28 weeks of pregnancy. Combining ANGPTL8 levels with conventional risk factors can improve the predictive ability for GDM[14,15]. GDM affects about 14% of pregnant women worldwide. According to IADPSG diagnostic criteria, the International Diabetes Federation estimates that there are currently 18 million GDM patients, and this number is expected to rise with the obesity epidemic. Approximately 80% of pregnant women with diabetes have GDM, while less than 20% have pre-existing diabetes[16]. Pregnancy is a state of high metabolic activity, making the maintenance of glucose homeostasis crucial. When pancreatic β-cells cannot compensate for the chronic energy demands, leading to insulin resistance, hyperglycemia, and abnormal glucose supply to the growing fetus, GDM may occur[17]. RBP4 and ANGPTL8 may play a combined role in the pathogenesis of GDM, but there is still insufficient evidence to diagnose GDM solely by detecting these two proteins. Further research is needed to establish their diagnostic value.

CONCLUSION

Modern medicine emphasizes both precision and personalization, and research on GDM holds significant clinical and theoretical value. Damage to pancreatic islets β-cells and insulin resistance in tissue cells are key to the pathophysiology of GDM. Only through in-depth research on the pathogenesis of GDM can we hope to ultimately overcome this disease. Introducing advanced biotechnologies, such as proteomics, for basic research on GDM is a promising approach. In the future, it will be essential to collect more blood samples from GDM patients and track several relatively specific proteins to continue this line of research. This will enable a deeper understanding of GDM and the development of more effective diagnostic and therapeutic strategies.